A central challenge for gene therapy is the effective delivery of highly labile nucleic acids that are susceptible to nucleases. While there are examples of successful nucleic acid delivery in vitro and in vivo by viral and non-viral vectors, achieving high transfection efficiency while maintaining low toxicity remains a significant challenge. Although virus-mediated vehicles are efficient in gene transduction, they exhibit severe immunogenic properties and can cause detrimental mutagenic responses rendering them problematic.
Considerable effort has been made to develop non-viral vectors such as cationic lipids, cationic polymers, and cell-penetrating peptides (CPPs). Cationic lipids form non-covalent complexes with nucleic acids to generate lipoplexes. However, as the condensation ability of lipids alone is not effective, the resulting lipoplexes do not protect genes against nucleases in vivo. Cationic polymers such as polyethylenimine (PEI), poly (L-lysine) (PLL), polyamidoamine (PAMAM) dendrimers and polymethacrylates form particulate complexes with DNA producing polyplexes that can deliver genes. Although such polyplexes demonstrate r transfection ability, they exhibit high cytotoxicity. Moreover, chemical modifications to the cationic polymers are required to reduce their cytotoxicity. The resultant chemically modified polymers demonstrate decreased transfection ability. While CPPs have been explored for their ability to deliver nucleic acids, delivery remains a major challenge (Fonseca et al. Adv Drug Deliv Rev. 2009; 61:953-64) due to entrapment into endocytic vesicle and lysosomal degradation (Richard et al., J Biol Chem. 2003; 278:585-90; Al-Taei et al., Bioconjug Chem. 2006; 17:90-100. Recently, lipopolyplexes composed of a cationic lipid and cationic peptide-based ternary complex have been introduced to enhance transfection of nucleic acids (Zuhorn et al., Eur Biophys J. 2007; 36:349-62; Chen et al., Mol Pharm. 2009; 6:696-705). While lipopolyplexes have been employed for gene delivery, it depends on the development of branched systems carrying a net positive charge (Weiser et al., Mol Pharm. 2013; 10:127-41); in such cases, identifying optimal branching, charge and sequence will require various synthetic design strategies.